Field of the Invention
The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to certain di-isopropyl-phosphinoyl-alkanes as described herein (DIPA-5, DIPA-1-6, DIPA-1-7, DIPA-1-8, and DIPA-1-9, collectively referred to herein as “DIPA compounds”) that are useful, for example, in the treatment of disorders (e.g., diseases) including: sensory discomfort (e.g., caused by irritation, itch, or pain); a skin dysesthesia; atopic dermatitis; ocular pain and discomfort; heat discomfort; heat stress; flushing and/or night sweats (vasomotor symptoms); post-operative hypothermia; post-anaesthetic shivering; fatigue; tiredness; depression; cognitive dysfunction; and to enhance cognitive function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example, in therapy, diagnosis, and laboratory investigations. The unusual property of the DIPA molecules is the ability to penetrate the keratinized layers of the skin [stratum corneum] to reach receptive targets underneath.
Description of Related Art
Heat abstraction from the body's surfaces can refresh the senses, relieve discomfort, attenuate pain, and suppress inflammation. Abstraction of heat from body surfaces evokes sensations that are termed cool, refreshing cool, chilly, cold, icy cold and painful cold. For example, air blown onto the face from a fan or an air-conditioner can reduce tiredness and increase alertness. A wet towel applied to the forehead can relieve discomfort from a fever or a headache. The methods of heat abstraction, with gas, liquids, or solids, achieve their effects by physically lowering tissue temperatures and by activating signals to the brain.
Chemical sensory/cooling agents are molecules that can mimic the sensations of heat abstraction without a change in tissue temperatures. The exact sensations produced by chemicals depend on the selection of the active ingredient and the site and method of delivery. With most of the agents currently in use, some degree of chemical cooling on the scalp and skin of the face, nostrils, and philtrum can be elicited, but the effects do not last long. For the skin of the torso and limbs overt sensations of coolness and cold are more difficult to elicit and sustain. The skin has a keratinized layer of dead cells, called the stratum corneum, that is a formidable barrier to drug penetration into the epidermis and dermis. The neuronal receptive fields to detect temperature changes are located in the skin sub-layers.
The term “chemical cooling agent” can be ambiguous because, for example, chemicals such as ethyl chloride as a gas, ethanol as a liquid, liquid nitrogen, or carbon dioxide as a solid, applied to the skin can evoke heat abstraction sensations by reducing tissue temperatures. In this application, chemical cooling agents will refer only to agents that elicit sensations of heat abstraction without a lowering of tissue temperatures.
The inventor has previously identified several p-menthane carboxamide compounds that, when applied to the philtrum skin, simulate effects of heat abstraction for >1.5 hr without decreasing tissue temperature (Wei, E T. Sensory/cooling agents for skin discomfort. Journal Skin Barrier Research 14: 5-12, 2012). These compounds are relatively water-insoluble.
“Thermal comfort” is a well-developed concept in ergonomics, engineering, and architecture. The term refers to a condition in which a person wearing a normal amount of clothing feels neither too cold nor too warm. Thermal comfort is important for one's well-being and for productivity. It is achieved when the air temperature, humidity, and air movement are within a specified range called the “comfort zone” [24 to 27° C. for UK and USA]. It is has been known for some time that an environmental temperature below 21.1° C. (70° F.) is optimal for work performance, and that the best temperature is in the range of 18.3 to 20° C. (65 to 68° F.) (Dawson et al., 2009, “Nine switches of human alertness”, www.circadian.com, presentation from Circadian Technologies, Inc., Houston, Tex., USA, October 2009]. Experimentally, an improvement in performance can be demonstrated at 20° C. versus a 23° C. environment [Tham and Willem, Room air temperatures affects occupant's physiology, perceptions, and mental alertness. Building Environment 45: 40-44, 2010]. Conversely, careful studies have documented that work performance and productivity (output/input) drop by 2% for every increment of +1° C. above 25° C. up to 33° C. [Tanabe et al. Indoor environmental quality and productivity. Rehva Journal (Federation of the European Heating and Air Conditioning Associations) June, 2007]
The site where temperature is detected on the skin qualitatively affects perception of thermal comfort. Temperature sensitivity over the body surface varies over ˜100 fold. The face, especially area around the eyes [periorbital] and mouth [perioral] are very sensitive, but the extremities have poor sensitivity, and the rest of the body is intermediate [Stevens et al. Temperature sensitivity of the body surface over the life span. Somatosensory Motor Research 15: 13-28, 1998]. The sensory innervation of the periorbital and perioral regions are mediated by the V1 and V2 branches of the trigeminal nerve [5th cranial nerve].
In hot conditions, humans prefer a cool face, and in cold they prefer a warm abdomen. The human brain is particularly susceptible to heat damage and can only tolerate ˜40.5° C., while organs of the torso tolerate >42° C. Thus, a hot face would further heat an overheated brain, and preference for a low facial temperature in the heat has survival value [Nakamura et al. Relative importance of different surface regions for thermal comfort in humans. Eur. J. Applied Physiology, 113, 63-76, 2012]. Alleviating the sense of heat on the face can reduce discomfort and improve an organism's ongoing behavior. Facial cooling can also alert the organism and increase vigilance to focus on threats to its well-being. This fact is well-known to skiers and to people who live in countries with frigid winters.
Known Phosphine Oxides
The 1-dialkyl-phosphinoyl-alkanes [e.g. total number of carbons≦16] are solvent-like molecules that require only several [1 to 3] steps for synthesis. They are also known as trialkylphosphine oxides, but the preferred term now is dialkyl-phosphinoyl-alkane [DAPA]. If two of the alkyl groups are isopropyl, the DAPA could be abbreviated as DIPA [diisopropyl-phosphinoyl-alkane],
Rowsell and Spring [Phosphine oxides having a physiological cooling effect. U.S. Pat. No. 4,070,496. Jan. 24, 1978], describes a range of phosphine oxides which have a physiological cooling effect on skin and on the mucous membranes of the body, particularly the nose, mouth, throat and gastrointestinal tract. See, e.g., the table in columns 3 and 4 therein. Ten (10) of the compounds shown therein (Table 1) have one isopropyl group (shown as iso-C3H7). None of the compounds has two isopropyl group3.
TABLE 1Compounds in Rowsell et al., 1978P(═O)R1R2R3#R1R2R32n-C7H15iso-C3H7sec-C4H93n-C8H17iso-C3H7sec-C4H97n-C6H13iso-C3H7sec-C4H98n-C6H13iso-C3H7cyclo-C5H911n-C7H15iso-C3H7cyclo-C5H912n-C6H13iso-C3H7iso-C5H1115n-C7H15iso-C3H7iso-C5H1126n-C6H13iso-C3H7n-C6H1330n-C8H17iso-C3H7cyclo-C5H947iso-C3H7n-C4H9(n-C4H9)(C2H5)CHCH2
Wei, E. T. [Ophthalmic compositions and method for treating eye discomfort and pain. US 2005/0059639 A1, Mar. 17, 2005] describes the use of certain phosphine oxides and the treatment of eye discomfort by the administration of eye drops containing those compounds. See, e.g., Table 1 on page 4 therein. Five (5) of the compounds shown therein (Table 2) have one isopropyl group (shown as iso-C3H7).
TABLE 2Compounds in Wei, 2005P(═O)R1R2R3#R1R2R314n-C6H14iso-C5H11iso-C3H715n-C7H15iso-C5H11iso-C3H717n-C6H14iso-C3H7sec-C4H918n-C7H15iso-C3H7sec-C4H919n-C8H17iso-C3H7sec-C4H9
Siddall et al. [Simplified preparation of some trisubstituted phosphine oxides. J. Chemical Engineering Data 10: 303-305, 1965] reported the synthesis of 1-di-isopropyl-octane [DIPA-1-8]. Unlike the Tables 1 and 2 compounds, the DIPA-1-8 compound has two isopropyl groups. No reports on any bioactivity of such di-isopropyl compounds have previously been made.